Mutations and polymorphisms in the gene encoding regulatory subunit type 1‐alpha of protein kinase A (PRKAR1A): an update |
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| Authors: | Anélia Horvath Jérôme Bertherat Lionel Groussin Marine Guillaud‐Bataille Kitman Tsang Laure Cazabat Rosella Libé Elaine Remmers Fernande René‐Corail Fabio Rueda Faucz Eric Clauser Alain Calender Xavier Bertagna J Aidan Carney Constantine A Stratakis |
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| Institution: | 1. Section on Endocrinology and Genetics, Program in Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland;2. INSERM U567, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department, Paris, France;3. Université Paris‐Descartes, Paris, France;4. Assistance Publique‐H?pitaux de Paris, Department of Endocrinology, H?pital Cochin, Paris, France;5. Assistance Publique‐H?pitaux de Paris, Department of Biostatistics, H?pital Cochin, Paris, France;6. Genetics and Genomics Branch, NIAMS, Bethesda, Maryland;7. Laboratory of Molecular Genetics, Pontificia Universidade Catolica do Parana, Curitiba, Brazil;8. Unit on Genetics and Endocrine Tumors, CNRS UMR 5201, Claude Bernard University and CHU Lyon, Lyon, France;9. Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Ohio State University, Columbus, Ohio;10. Department of Laboratory Medicine and Pathology (emeritus member), Mayo Clinic, Rochester, Minnesota |
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| Abstract: | PRKAR1A encodes the regulatory subunit type 1‐alpha (RIα) of the cyclic adenosine monophosphate (cAMP)‐dependent protein kinase (PKA). Inactivating PRKAR1A mutations are known to be responsible for the multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in PRKAR1A have been identified (online database: http://prkar1a.nichd.nih.gov ). The majority are subject to nonsense mediated mRNA decay (NMD), leading to RIα haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIα haploinsufficiency, but also by the expression of altered RIα protein, as proven by analysis of expressed mutations in the gene, consisting of aminoacid substitutions and in‐frame genetic alterations. In addition, a new subgroup of mutations that potentially escape NMD and result in CNC through altered (rather than missing) protein has been analyzed—these are frame‐shifts in the 3′ end of the coding sequence that shift the stop codon downstream of the normal one. The mutation detection rate in CNC patients is recently estimated at above 60%; PRKAR1A mutation‐negative CNC patients are characterized by significant phenotypic heterogeneity. In this report, we present a comprehensive analysis of all presently known PRKAR1A sequence variations and discuss their molecular context and clinical phenotype. Hum Mutat 31:369–379, 2010. Published 2010 Wiley‐Liss, Inc. |
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| Keywords: | PRKAR1A PKA mutations polymorphisms Carney complex CNC |
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